1. Field of Invention
The inventive subject matter relates to a method of inducing immune allograft tolerance and chimerism.
2. Background Art
Activated T-cells orchestrate the rejection of vascularized allografts unless multiple components of an alloimmune response are indefinitely attenuated. These in vivo corrections are typically achieved through the long-term administration of potent immunosuppressive drugs that nonspecifically block T-cell activation, proliferation and function while trying to avoid the deleterious consequences of over immunosuppression (1, 2). In contrast, therapies to induce tolerance, which exploit the immune system's endogenous regulatory mechanisms through clonal deletion of alloreactive T-cells and the induction of donor CD4+ regulatory cell populations (Tregs) (3-5), have been more difficult to achieve. In various experimental animal models, T-cell depletion, T-cell costimulation blockade, and/or donor hematopoietic cell infusion/chimerism have been shown to promote organ specific immune tolerance after transplantation (1, 4, 6). However, clinical success has been limited and unpredictable (5, 7).
Recently, the immunoregulatory properties of a number of tissue mesenchymal stromal cells (MSC) or MSC-like populations, mainly bone marrow and adipose tissue-derived cells, have attracted a lot of attention as potential therapeutic cell sources for use in tolerance induction cell therapies. Human amnion epithelial cells (hAECs) derived from the embryonic epiblast, are immunologically tolerated cells suppress T-cell allogeneic proliferation responses in mixed lymphocyte reaction (MLR) cultures wherein hypo-responsiveness is mediated via cell-to-cell contact with target immune cells and secretion of soluble mediators (PGE-2 and TGFβ1) plus the inhibition of the differentiation and maturation of monocytes into dendritic cells (DCs) resulting in an impaired allostimulation function on T-cells (8-21). Here we show that the administration of AMPs combined with a clinically feasible regimen of CD4+/CD8+ cell depletion, low dose busulfan conditioning and limited numbers of unfractionated donor bone marrow cells result in stable multilineage donor cell chimerism induction, indefinite allograft acceptance, and donor cell specific tolerance in the absence of long-term immunosuppressive treatment.